ARTICLE OPEN ACCESS CLASS OF EVIDENCE

Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsyDileep R. Nair, MD, Kenneth D. Laxer, MD, Peter B. Weber, MD, Anthony M. Murro, MD, Yong D. Park, MD,

Gregory L. Barkley, MD, Brien J. Smith, MD, Ryder P. Gwinn, MD, Michael J. Doherty, MD,

Katherine H. Noe, MD, PhD, Richard S. Zimmerman, MD, Gregory K. Bergey, MD, William S. Anderson, MD, PhD,

Christianne Heck, MD, Charles Y. Liu, MD, PhD, Ricky W. Lee, MD, Toni Sadler, PA-C, Robert B. Duckrow, MD,

Lawrence J. Hirsch, MD, Robert E. Wharen, Jr., MD, William Tatum, DO, Shraddha Srinivasan, MD,

Guy M. McKhann, MD, Mark A. Agostini, MD, Andreas V. Alexopoulos, MD, MPH, Barbara C. Jobst, MD,

David W. Roberts, MD, Vicenta Salanova, MD, Thomas C. Witt, MD, Sydney S. Cash, MD, PhD, Andrew J. Cole, MD,

Gregory A. Worrell, MD, PhD, Brian N. Lundstrom, MD, PhD, Jonathan C. Edwards, MD, Jonathan J. Halford, MD,

David C. Spencer, MD, Lia Ernst, MD, Christopher T. Skidmore, MD, Michael R. Sperling, MD, Ian Miller, MD,

Eric B. Geller, MD, Michel J. Berg, MD, A. James Fessler, MD, Paul Rutecki, MD, Alica M. Goldman, MD, PhD,

Eli M. Mizrahi, MD, Robert E. Gross, MD, PhD, Donald C. Shields, MD, Theodore H. Schwartz, MD,

Douglas R. Labar, MD, PhD, Nathan B. Fountain, MD, W. Jeff Elias, MD, Piotr W. Olejniczak, MD, PhD,

Nicole R. Villemarette-Pittman, PhD, Stephan Eisenschenk, MD, Steven N. Roper, MD, Jane G. Boggs, MD,

Tracy A. Courtney, BS, Felice T. Sun, PhD, Cairn G. Seale, MS, Kathy L. Miller, BS, Tara L. Skarpaas, PhD, and

Martha J. Morrell, MD, on behalf of the RNS System LTT Study

Neurology® 2020;95:e1244-e1256. doi:10.1212/WNL.0000000000010154

Correspondence

Dr. Morrell

mmorrell@neuropace.com

AbstractObjectiveTo prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adultswith medically intractable focal onset seizures (FOS) over 9 years.

MethodsAdults treated with brain-responsive neurostimulation in 2-year feasibility or randomizedcontrolled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety,efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverseevents (AEs), efficacy as median percent change in seizure frequency and responder rate, andQOL with the Quality of Life in Epilepsy (QOLIE-89) inventory.

ResultsOf 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the medianpercent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responderrate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-upand an average seizure-free period of 3.2 years (range 1.04–9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). Therewere no serious AEs related to stimulation, and the sudden unexplained death in epilepsy(SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed χ2).

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From the Cleveland Clinic Foundation (D.R.N., A.V.A.), OH; California Pacific Medical Center (K.D.L., P.B.W.), San Francisco; Augusta University (A.M.M., Y.D.P.), GA; Henry FordHospital (G.L.B.), Detroit, MI; Ohio Health Neuroscience (B.J.S.), Columbus; Swedish Neuroscience Institute (R.P.G., M.J.D.), Seattle, WA; Mayo Clinic Arizona (K.H.N., R.S.Z.), Scottsdale;Johns Hopkins Medicine (G.K.B., W.S.A.), Baltimore, MD; Keck School of Medicine of USC (C.H., C.Y.L.), Los Angeles, CA; Via Christi Epilepsy Center (R.W.L., T.S.), Wichita, KS; YaleUniversity School of Medicine (R.B.D., L.J.H.), New Haven, CT; Mayo Clinic Florida (R.E.W., W.T.), Jacksonville; Columbia University Medical Center (S.S., G.M.M.), New York, NY;University of Texas Southwestern Medical Center (M.A.A.), Dallas; Geisel School of Medicine at Dartmouth (B.C.J., D.W.R.), Hanover, NH; Indiana University School of Medicine (V.S.,T.C.W.), Indianapolis; Massachusetts General Hospital (S.S.C., A.J.C.), Boston; Mayo Clinic Minnesota (G.A.W., B.N.L.), Rochester; Medical University of South Carolina (J.C.E., J.J.H.),Charleston; Oregon Health & Science University (D.C. Spencer, L.E.), Portland; Thomas Jefferson University (C.T.S., M.R.S.), Philadelphia, PA; Nicklaus Children’s Hospital (I.M.), Miami,FL; Saint Barnabas Medical Center (E.B.G.), Livingston, NJ; University of Rochester Medical Center (M.J.B., A.J.F.), NY; University of Wisconsin Hospital and Clinics (P.R.), Madison; BaylorCollege of Medicine (A.M.G., E.M.M.), Houston, TX; Emory University School of Medicine (R.E.G.), Atlanta, GA; George Washington University School of Medicine and Health Sciences(D.C. Shields), Washington, DC; Weill Cornell Medical College (T.H.S., D.R.L.), New York, NY; University of Virginia School of Medicine (N.B.F., W.J.E.), Charlottesville; Louisiana StateUniversity Health Sciences Center (P.W.O., N.R.V.-P.), New Orleans; University of Florida (S.E., S.N.R.), Gainesville; Wake Forest University Health Sciences (J.G.B.), Winston-Salem, NC;NeuroPace, Inc (T.A.C., F.T.S., C.G.S., K.L.M., T.L.S., M.J.M.), Mountain View; and Stanford University (M.J.M.), Palo Alto, CA.

Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

Coinvestigators are listed at links.lww.com/WNL/B153.

The Article Processing Charge was funded by the authors.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloadingand sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

e1244 Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

ConclusionsAdjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS withimproved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; andSUDEP rates were low.

ClinicalTrials.gov identifierNCT00572195.

Classification of evidenceThis study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptablesafety over 9 years.

About 30% to 40% of patients with epilepsy are refractory tomedications.While resective or ablative procedures provide the bestlikelihoodof seizure freedom,1–3 these approaches are not anoptionfor many patients due to the potential for neurologic risk or in-sufficient likelihood of benefit. Neuromodulation approaches, in-cluding vagus nerve stimulation4,5 (VNS), deep brain stimulation6,7

(DBS), and brain-responsive neurostimulation8–10 (RNS System,NeuroPace, Inc), have been demonstrated to be safe and effectivetreatments to reduce seizure frequency for these patients. In con-trast toDBS, brain-responsive neurostimulation delivers stimulationonly in response to changes in ongoing neural activity at the seizurefocus.8–10 While this approach requires the identification of theseizure focus, it limits the amount of stimulation delivered perday.8–10

The RNS System is approved by the US Food and Drug Ad-ministration (FDA) as an adjunctive treatment for adults withmedically refractory focal onset seizures arising from 1 or 2 seizurefoci.8–10 An initial 2-year feasibility study (n = 65) demonstratedsafety and provided preliminary evidence of effectiveness, anda 2-year double-blinded randomized controlled trial (n = 191)demonstrated safety and effectiveness. Final results are providedfrom an FDA-requested and -approved prospective open-labellong-term treatment (LTT) clinical study intended to collect anadditional 7 years of prospective data on the safety and effective-ness of the RNS System. This report of 9 years of patient follow-upsupplements and extends the experience and observations pre-sented in an interim analysis8 and represents the largestmulticenterprospective trial in the field of neuromodulation to date.

MethodsThe RNS System (NeuroPace, Inc, Mountain View, CA)provides brain-responsive (closed-loop) neurostimulation

when abnormal electrocorticographic (ECoG) activity isdetected, typically epileptiform activity that is observed at theonset of electrographic seizures. As described in a prior publi-cation,11 a cranially implanted programmable neurostimulatoris connected to depth or subdural cortical strip leads that areplaced according to the patient’s previously identified seizurefocus or foci. Each lead contains 4 electrode contacts (figure 1).Two leads can be connected to the neurostimulator at a time,and as many as 4 leads could be implanted in the clinical trials(nomore than 2 depth leads). The neurostimulator continuallysenses ECoG activity through the electrodes and is pro-grammed by the physician to detect specific ECoG patternsand to deliver stimulus pulses in response to detections. Thephysician adjusts detection and stimulation parameters for eachpatient as needed for seizure reduction.8

The LTT study was open to patients who participated in the2-year feasibility or pivotal studies beginning in 2004 andcompleted in 2018. Patients were followed up for an addi-tional 7 years. Adverse event (AE) and daily seizure diary datawere collected every 6 months at a minimum. Quality of life(QOL) was assessed yearly by the Quality of Life in Epilepsy(QOLIE-89).12 Safety was assessed as spontaneously repor-ted AEs, which were categorized by the investigator as mild orserious and as device related, of uncertain device relation, ornot device related. An independent data monitoring com-mittee reviewed all AEs. All deaths were also evaluated bya sudden unexplained death in epilepsy (SUDEP) analysiscommittee that adjudicated whether the death was possibly,probably, or definitely related to SUDEP or not SUDEP.

Efficacy was assessed as median percent change in seizurefrequency and as responder rate (the percentage of patientswith a ≥50% reduction in seizure frequency) for each 6-month

GlossaryAE = adverse event; CI = confidence interval;DBS = deep brain stimulation; ECoG = electrocorticographic; FDA = Food andDrug Administration; GEE = generalized estimating equation; IQR = interquartile range; LOCF = last observation carriedforward; LTT = long-term treatment; QOL = quality of life; QOLIE-89 = Quality of Life in Epilepsy; SAE = serious AE;SUDEP = sudden unexplained death in epilepsy; VNS = vagus nerve stimulation.

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period compared to the prospective preimplantation baselinefor patients with a minimum diary requirement of 91 recordeddays per 182-day period (≥91 days diary requirement). Thesignificance of the reduction in seizure frequency at each timepoint was assessed with the Wilcoxon signed rank test (α <0.05). The robustness of the efficacy outcome was tested withseveral different analysis approaches, including a constant

cohort (data at each time point from all patients who com-pleted the trial) analysis and a last observation carried forward(LOCF) analysis. If improvements in seizure frequency overtime were driven primarily by patient dropout, then themedianpercent reduction for the constant cohort, LOCF populations,or both would be expected to remain similar at all time points.

To test whether there was continued improvement in seizurefrequency over time, the percent change in seizure frequency foreach 6-month period was modeled with a generalized estimatingequation (GEE)model with time (defined as 0, 1, 2, 3…for eachconsecutive 6-month period beginning with months 6–12 as thefirst period). For each participant, only periods with at least 91 of182 days of seizure diary data were included; the remainingperiods were considered missing data. The GEE model useda compound symmetry correlation structure to account for re-peated measurements per participant over the course of thestudy. In this model, the estimated value of the intercept wasinterpreted as the estimated percent change in the first 6-monthperiod (months 6–12). The estimated value of the slope wasthen interpreted as the estimated linear change in the percentchange in seizure frequency over the remaining periods (α <0.05). Additional GEE models were performed on subgroups toassess whether clinical covariates such as age at enrollment (bymedian split), age at onset (by median split), prior surgery forepilepsy (yes/no), prior intracranial monitoring (yes/no), priorVNS (yes/no), abnormality on brain MRI (yes/no), number ofseizure onset zones (1/2), and seizure onset location (mesialtemporal lobe/neocortical/both) were predictive of outcome.

Antiseizure medications could be adjusted as medically neces-sary. The impact of changing antiseizure medications on theclinical outcomes at the last follow-up was compared to baseline.An increase in antiseizure medications was defined as a ≥25%increase in dose, the addition of a medication not taken atbaseline, or both. A decrease was defined as a ≥25% reduction indose, the discontinuation of an antiseizure medication, or both.Patients in the mixed category had both a qualifying increase in≥1 medications and a qualifying decrease in ≥1 medications.Patients in the no change categorywere on the samemedicationsand doses (±<25%) at the last follow-up as at baseline. Thereduction in clinical seizure frequency during the last 6 monthsof follow-up using the LOCF population was then comparedbetween the patients in the 4 groups (increase, decrease, mixed,or no change) with the Wilcoxon rank sum tests (α < 0.05).

Average changes in the QOLIE-89 overall T score and 4subdomains of QOL were compared to the preimplantationbaseline with a paired t test.

Neurostimulator battery longevityA Kaplan-Meier survival analysis was used to estimate themedian survival of the RNS-300M (the neurostimulatormodel primarily used in the LTT study). The analysis in-cluded all RNS-300M devices implanted through April 2019and excluded devices explanted for reasons other than batterydepletion (e.g., infection or lead revision).

Figure 1 RNS System

Left, RNSneurostimulator andNeuroPace cortical strip anddepth leads. Topright, record of the number of electrographic events detected by the neu-rostimulator over time for an individual patient. Bottom right, snapshots ofelectrographic activity recorded by the RNS System for an individual patient.Copyright © 2020 NeuroPace, Inc.

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Standard protocol approvals, registrations,and patient consentsAll study protocols were approved by the FDA and the in-stitutional review boards of the participating investigationsites. All participants gave written informed consent. TheLTT study is registered on clinicaltrials.gov (NCT00572195).

Classification of evidenceThis prospective open-label study provides Class IV evidencethat brain-responsive neurostimulation is acceptably safe,reduces seizure frequency, and improves QOL in adults withmedically refractory focal onset seizures over a mean follow-up of 7.5 years (range 5 weeks–11.2 years; median follow-up8.97 years). One hundred seventy-three of the participantswere part of the original randomized double-blinded trial thatprovided Class I evidence for safety and effectiveness.

Data availabilityNo data are available.

ResultsTwo hundred fifty-six participants were initially implantedwith the RNS Neurostimulator and NeuroPace leads withinthe feasibility and pivotal studies combined; 230 enrolled inthe LTT study, and 162 completed all 9 years of follow-up.This provides an accumulated experience of 1,895 patient-implantation years and 1,788 years over which brain-responsive neurostimulation was enabled. The mean follow-up period was 7.5 years (SD 2.9 years, range 5 weeks–11.2years), and the median follow-up was 8.97 years. Subject ac-countability is provided in figure 2.

Subject demographics and clinical characteristics for allimplanted participants are provided in table 1. The partic-ipants had experienced frequent seizures (mean ± SD seizurefrequency per month 50.7 ± 177.4) for many years (mean ±SD duration of epilepsy 19.7 ± 11.4 years). One-third hadbeen treated with VNS and one-third with epilepsy surgery.

Efficacy

Device settingsOver the 9 years of follow-up, patients received an average of1,028 detections per day (range 5–3,091). The most commonstimulation therapy settings were 2 bursts of stimulation at 100to 200 Hz, 160-microsecond pulse width, and 100-millisecondburst duration with the majority of detections resulting in thedelivery of a single therapy. Thus, for this cohort, the maximumamount of stimulation delivered per day was 10.3 minutes withpatients receiving on average 3.4minutes of stimulation per day.

Seizure reductionSeizure reductions in 6 months intervals were statistically signifi-cant over the entire 9 years of follow-up compared to baseline.Figure 3A shows the median seizure frequency change from

baseline during theLTTstudy (3–9 years after implantation). Thereduction in seizures is displayed for the population who met the91-day minimum diary requirement, a constant cohort, and anLOCF population. The reduction in seizures improved over theadditional 7 years of follow-up. Based on the 91-day minimumdiary requirement population, themedian percent reduction at theend of year 3 was 58%. This improved steadily, reaching 75% bythe end of 9 years of treatment (p < 0.0001, Wilcoxon signedrank). Similar results were observed with the other analysisapproaches, suggesting that the improvement over time was notdue to enrichment in the patient population (figure 3A). In the 91-day seizure diary requirement population, the GEE estimateda statistically significant continued reduction in seizures of 1.2%per 6-month period over time (p < 0.001). Figure 3B shows thedistribution of individual responses to treatment at 9 years forparticipants with at least 91 days of seizure diary data; the re-sponder rate was 73%; 35% had a ≥90% reduction in their seiz-ures; and 21% were seizure-free in the last 6 months of follow-up.

Seizure reductions and clinical covariatesThe slope of the median percent reduction in seizure fre-quency over time was not influenced by any of the clinicalcovariates. The improvement in themedian percent reductionin seizure frequency was similar for participants with andwithout prior epilepsy surgery (p = 0.33), VNS (p = 0.70), orintracranial monitoring (p = 0.39). In addition, the reductionin seizure frequency over time was not influenced by theparticipant’s age at enrollment (p = 0.26), age at seizure onset(p = 0.24), the presence or absence of any brain abnormalityon imaging (p = 0.51), the seizure onset location (p = 0.34), orthe number of seizure foci (p = 0.20).

Figure 2 RNS System studies, participant accountability

aFeasibility study: 6 participants discontinued before completing the study; 2participants completed the study but elected not to enroll in the long-termtreatment (LTT) study. Thus, 57 participants in the feasibility study enrolledin the LTT study. bPivotal study: 16 participants discontinued before com-pleting the study; 4 participants completed the study but elected not toenroll in the LTT study. Two participants who discontinued early weregranted waivers and were allowed to enroll, resulting in 173 pivotal partic-ipants enrolling into LTT. A total of 230 participants chose to enroll in the LTTstudy, and 162 participants completed the study. cReasons for early with-drawal from the LTT study included the following: chose not to replaceneurostimulator (n = 20); to pursue other treatment options (n = 10); in-sufficient efficacy (n = 8); study noncompliance (n = 7); and to receivemedicalcare at a nonstudy center (n = 5).

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Seizure reductions and antiseizure medicationsAntiseizure medications were adjusted in many patients overthe open-label follow-up, as was allowed in the protocol (table2). There were no statistically significant differences in theefficacy endpoints at last follow-up between patients who hadan addition or increase in antiseizure medications, patientswho had a decrease, and those who had no change (p > 0.05).

Seizure reductions and lobe of seizure onsetIn addition, median percent seizure reductions at 9 years weresimilar for participants with seizure onsets in themesial temporallobe, unilateral or bilateral (73%; interquartile range [IQR]58%–96%; n = 66), or in the neocortex (81%; IQR 34%–100%;n = 70), including frontal lobe (93%; IQR 31%–100%; n = 21),and other regions of the neocortex (79%; IQR 52%–93%; n =30). Seizure reductions for each onset region are provided intable 3.

Seizure freedomOver the 9 years of follow-up, many patients experienced pro-longed seizure-free periods (figure 3C); 28.1% (72 of 256) had atleast 1 seizure-free period of ≥6 months, while 18.4% (47 of 256)had at least 1 seizure-free period of ≥1 year. For patients with atleast 1 year of seizure freedom, the average duration of their longestconsecutive period of seizure-free days was 3.2 years (range1.04–9.6 years). At the completion of the study, 62% (29 of 47) ofpatients with ≥1 year of seizure freedom were also seizure-freeduring the last year of follow-up.

Quality of lifeOverall QOLIE-89 scores improved at 1 year (n = 212, mean3.2, SD 8.6, p < 0.0001), and improvements were maintainedthrough year 9 of treatment (n = 145, mean 1.9, SD 11.1,

p < 0.05), as were statistically significant improvements inepilepsy targeted (n = 145, mean 4.5, SD 10.4, p < 0.001) andcognitive (n = 145, mean 2.5, SD 10.5, p = 0.005) domains.

Safety

Device-related serious AEsOver the entire follow-up, the only device-related serious AEs(SAEs) that were reported in ≥5% of patients cumulatively wereimplantation site infection and elective explantation of the neuro-stimulator, leads, or both.The risk of infectionper procedure (initialimplantation, replacement, or revision) was 4.1%. Over the cu-mulative 1,895 patient-implantation years, serious device-relatedimplantation site infection was reported in 12.1% of participants.The events were typically reported shortly after a surgical procedure(median 36 days; range 0–1,261 days), and 16 of the 35 infectionsled to a device explantation. All but 1 of the infections involved onlysoft tissue, and cultures most often indicated skin flora; there wereno instances of meningitis or brain parenchymal infection.13,14

Other device-related SAEs included non–seizure-related hemor-rhage in 7 patients (2.7%), 4 of which occurredwithin a fewdays ofan implantation procedure and had no neurologic sequelae. Statusepilepticus occurred in 8.2% of participants during the study; 52%(15 of 29) of the events were nonconvulsive status epilepticus. Themajority of these events were not device related (26 of 29) andwere considered serious (27 of 29) due to hospitalization.

Depression and suicidalityAt enrollment in the RNS System studies, 60% of all participantsreported a medical history of depression, suicidality, or both.Cumulatively, 1.6% (4 of 256) of participants reported an SAErelated to depression, and 23.4% (60 of 256) reported amild AE;the majority of these participants (71%) had a medical history ofdepression. The majority of AEs associated with depression(82%) were not considered to be device related.

AEs related to suicidality (suicidal depression, suicidal idea-tion, suicidal behavior, and suicide attempts) were reported in9.8% of participants over the 9 years; 68% of the events wereconsidered serious, and the majority of these participants(86%) had a history of depression. In addition, 2 patientscompleted suicide, 1 of whom was being treated with brain-responsive neurostimulation at the time. Both had a history ofdepression, and 1 also had a history of suicidality.

MemoryOnly 1 participant reported an SAE related to memory. Cu-mulatively, 12.5% of patients had a non–device-related AE(typically mild) related to memory impairment over the 9years. AEs related to memory impairment occurred most of-ten in patients who reported memory impairment beforeenrollment (69%).

SUDEP findingsThere were 16 deaths in the 256 patients over the 9 years offollow-up: 2 due to suicide; 1 each due to status epilepticus,

Table 1 Demographics and characteristics of allparticipants with implantations (n = 256)

Female, % (n) 49 (125/256)

Age,a mean ± SD (range), y 34.0 ± 11.3(18–66)

Duration of epilepsy,a mean ± SD (range), y 19.7 ± 11.4(2–58)

AEDs,a mean ± SD (range), n 2.9 ± 1.1 (0–8)

Preimplantation disabling seizures per month, mean± SD (median), n

50.7 ± 177.4(10.2)

Prior intracranial monitoring, % (n) 65 (166/256)

Prior epilepsy surgery, % (n) 34 (86/256)

Prior VNS, % (n) 32 (82/256)

Two seizure foci (vs one), % (n) 48 (124/256)

Mesial temporal lobe only onsets (vs other), % (n) 43 (111/256)

Abbreviation: AED = antiepileptic drug; VNS = vagus nerve stimulation.a At enrollment in initial study (feasibility or pivotal).Copyright © 2020 NeuroPace, Inc.

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herpes encephalitis, sepsis, lung/colon cancer, and lym-phoma; 4 due to definite SUDEP; 2 due to probable SUDEP;and 3 due to possible SUDEP. Two of the patients who hadSUDEP were not being treated with brain-responsive neu-rostimulation at the time of death. The rate of probable or

definite SUDEP combined was 2.8 per 1,000 patient-stimulation years (95% confidence interval [CI] 1.2–6.7)and 3.2 per 1,000 patient-implantation years (95% CI1.4–7.0). This is lower than the prespecified comparator of 9.3per 1,000 patient-years for patients who are epilepsy surgery

Figure 3 RNS System long term clinical response

Plot showing themedian percent reduction ± IQR in seizure frequency for the last 6months of each year in the long-term treatment study (years 3 through 9of treatment) compared to baseline for the 91-dayminimum diary requirement population, the constant cohort population, and the last observation carriedforward (LOCF) population. (A)Median percent reduction ± interquartile range (IQR) over time. (B) Individual changes in clinical seizure frequency. Changes inclinical seizure frequency during the last 6 months of follow-up before the year 9 visit for each participant who had at least 91 days of seizure diary data.Negative values indicate a seizure frequency reduction compared with baseline. (C) Bar graph showing the percent of all participants (All) and participantswith onsets in the mesial temporal lobe (MTL) or neocortex (Neo) with at least 1 period of seizure freedom lasting at least 3, 6, and 12 months.

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candidates and statistically significantly lower than the com-parator of 6.9 per 1,000 patient-years for patients with med-ically intractable epilepsy in the placebo arm of randomizedcontrolled medication trials (p < 0.05, 1-tailed χ2).15

Neurostimulator battery longevityThe Kaplan-Meier survival analysis of the RNS-300M neuro-stimulator model found the median time to replacement to be≈1,284 days or 3.5 years. For the RNS-300M neurostimulator,there were no device malfunctions related to the battery.

DiscussionTreatment with the RNS System significantly and progressivelyimproved seizures over 9 years of prospective follow-up. At thecompletion of 9 years of treatment, the median percent seizurereduction was 75%, the responder rate was 73%, andmore thanone-third of patients had a ≥90% reduction in seizures. Unlikeantiepileptic medications,16 the clinical response to brain-responsive neurostimulation improved over time. The analysisof the completed study showed a progressive improvement inseizure frequency through the end of 9 years of treatment. Thiscontrasts with the previously published interim analysis8 thatfound improvement in seizure frequency through the first 2

years followed by a plateau in response. The discrepancy islikely due to the smaller sample size at later time points in theinterim analysis while the study was ongoing. The progressiveimprovement through 9 years of follow-up is consistent withother neuromodulation modalities7 and suggests that therecould be longer-term neuromodulatory effects of neuro-stimulation that result in continued improvement in outcomes.

Many patients had long seizure-free periods. At the comple-tion of the study, 21% of patients were seizure-free. Over thecourse of the study, 28% of patients were seizure-free for atleast 1 period of ≥6 months, and 18% had at least 1 period of≥12 months without seizures. In addition, patients with atleast 1 year of seizure freedom experienced an average periodof 3.2 years without a seizure. These results are especiallymeaningful when we consider that these patients had a nearly20-year history of epilepsy, had >10 disabling seizuresa month at baseline, and had failedmultiple epilepsy therapies.

Significant seizure reductions were similarly likely in patientswith and without prior brain resective surgery, VNS, or in-tracranial monitoring; in patients with seizures arising fromthe mesial temporal lobe or neocortex; for those with 1 or 2foci; and for those with and without a lesion on brain MRI.

Table 2 LOCF seizure frequency reduction and responder rates based on antiseizure medication changes

Changes in antiseizure medications No. Median changea (IQR), % Responder rate,a % (n/N)

No change 22 −71 (−35 to −92) 64 (14/22)

Increase 52 −68 (−12 to −82) 63 (33/52)

Mixed (increase and decrease) 139 −73 (−32 to −97) 68 (94/139)

Decrease 16 −96 (−61 to −100) 75 (12/16)

Abbreviations: IQR = interquartile range; LOCF = last observation carried forward.a LOCF most recent 6 months of follow-up.Copyright © 2020 NeuroPace, Inc.

Table 3 Seizure frequency reduction and responder rates at 9 years according to region of seizure onset

Region of seizure onset Median reduction (IQR), % Responder rate, %

All MTL (n = 66) 73 (58–96) 77

MTL bilateral (n = 48) 71.9 (56–90) 77

MTL unilateral (n = 18) 94 (64–100) 78

All temporal (n = 95) MTL, lateral, MTL + lateral 73 (47–93) 72

All neocortical (n = 70) 81 (34–100) 70

Lateral temporal (n = 19) 81 (33–99) 58

Frontal (n = 21) 93 (31–100) 71

Other (n = 30) 79 (52–93) 77

Abbreviations: IQR = interquartile range; MTL = mesial temporal lobe.Copyright © 2020 NeuroPace, Inc.

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The reduction in seizures with RNS System treatment wasnot significantly associated with changes in antiseizuremedications. While there were no apparent differences inseizure frequency reductions for these different subgroups inthe clinical study, it should be noted that the study was notpowered for subgroup comparisons. As a result, largersample sizes may be needed to identify the characteristics ofpatients who are most likely to benefit from brain-responsiveneurostimulation.

The response to treatment with the RNS System is supportedby significant and sustained improvements in overall QOLand in individual domains of QOL that indicate less vulner-ability to seizures and a more positive perception of cognitivefunction. These are areas of function that are often profoundlyaffected in persons with intractable seizures.17,18

Responsive neurostimulation was well tolerated and safe overtime. AEs related to the implanted device, including infection,were anticipated, and the rates were not higher than reportedwith implantation of intracranial electrodes to localize the sei-zure focus,19–21 with resective epilepsy surgery,19,22,23 or withDBS devices for treatment of movement disorders24 or forepilepsy.6,7

Deaths, including deaths by SUDEP, were not more fre-quent than is expected in patients with medically intractablefocal onset seizures,25,26 and the SUDEP rate was signifi-cantly lower than the prespecified comparator estimate of9.3 per 1,000 patient years. An analysis of SUDEP events ina larger population of patients treated with the RNS System(n = 707) provides a more confident estimate of the SUDEPrisk, with a rate of probable and definite SUDEP of 2.0 per1,000 patient-stimulation years (95% CI 0.9–5.4).27

The risk for infection is 4.1% with each RNS Neurostimulatorprocedure and was previously shown not to increase withsubsequent routine neurostimulator replacements.13 Thiscompares favorably to other neurostimulation therapies thatuse a pectorally implanted pulse generator such as VNS28 andDBS for Parkinson disease24 or epilepsy.6,7

Depression comorbidity in patients with medically intractablefocal onset seizures reaches 66%.29 Validated inventories ofdepression (Beck Depression Inventory, Center for Epide-miologic Studies Depression) showed that there was no de-terioration in mood in patients treated with the RNS Systemduring the randomized controlled trial,10 and there weremodest group improvements.30 Patients in the RNS Systemtrials who had a history of depression, suicidality, or both weremore likely to experience AEs related to depression orsuicidality.

AEs related to memory impairment were infrequent inpatients treated with brain-responsive neurostimulation, werealmost all mild, and were predominantly from patients witha history of memory impairment.

In the RNS System randomized controlled trial, there was nodeterioration in any of 14 cognitive domains over 2 years.Verbal fluency improved significantly in patients with seizureonsets in neocortical regions. In addition, there were small butstatistically significant improvements in verbal memory thatwere specific to patients with seizures arising from the mesialtemporal lobe.31 These results contrast sharply with memoryoutcomes after temporal lobectomy or selective amygdalo-hippocampectomy, after which significant declines in verbalmemory may occur, particularly following dominant hemi-sphere procedures.32,33 Small but statistically significant cog-nitive declines in verbal and narrative memory have also beenreported after laser interstitial thermal therapy for mesialtemporal lobe epilepsy, particularly in the dominanthemisphere.34

The neurostimulator battery longevity for the RNS-300Mmodel observed in the clinical trial was consistent with thatanticipated by the battery longevity estimates provided in theuser manual, which indicates a time to end of service of 2.6 to4.2 years, depending on the device settings.35 This is shorterthan observed for the Kinetra and Activa-PC DBS neuro-stimulators on the basis of experience in Parkinson disease forwhich the median survival was 6.5 and 4.6 years, re-spectively.36 However, the newest neurostimulator model(RNS-320) is anticipated to increase battery longevity to 8years at moderate stimulation use.

While the RNS System provides a considerable amount ofambulatory ECoG data that necessitate interpretation by thephysician, these ECoG data may provide insights relevant tothe clinical care of persons with epilepsy. For example, RNSSystem long-term ECoG data have been used to refine lo-calization of the seizure onset and to inform decisions aboutresective or ablative surgery.37–39 ECoG data may provide anearly indication of the clinical response to antiseizure medi-cations40 and to changes in lifestyle.41 In addition, recentstudies have shown that features in the ECoG data mayprovide objective biomarkers that can be used to assess theclinical response to stimulation.42,43 In addition, it may bepossible to use an individual patient’s ECoG data to identifyperiods of heightened seizure risk.44,45 In the future, thesedata may be used to supplement the patient’s clinical report.However, these potential biomarkers require further researchand validation before they can be widely used in the RNSSystem patient population.

The results are provided from an open-label long-term studyand may be influenced by selection bias, expectation bias,a prolonged placebo response, or regression to the mean.However, a significant improvement was evident in treatedpatients compared to sham-stimulated patients in the blindedportion of a randomized controlled trial, and an improvement inthe sham-stimulated patients was evident when stimulation wasfirst provided, despite maintenance of the randomization blind.In addition, these patients had a 20-year history of intractableepilepsy on average, so it is unlikely that sustained and

Neurology.org/N Neurology | Volume 95, Number 9 | September 1, 2020 e1251

significant 9-year reductions would be observed. Finally, suchlong-term experience could not be feasibly obtained in a blindedand randomized trial.

The long-term efficacy and safety of brain-responsive neuro-stimulation for the treatment of medically intractable focalseizures are established on the basis of results in 256 patientswho were followed up prospectively for a median of 9 years. Aswith all other epilepsy therapies, there was a range of patientresponses. However, this study provides substantial evidencethat adjunctive treatment with brain-responsive neuro-stimulation is safe and provides persons with medically in-tractable focal epilepsy an opportunity for significant andsustained reductions in disabling seizures with enduringimprovements inQOL, as well as SUDEP rates that were lowerthan anticipated for similar patient populations. The safety ofthe surgical procedure and the implanted device compares fa-vorably to other brain stimulation devices used for the treat-ment of movement disorders24 and epilepsy.7

Future research will explore methods by which brain-responsive neurostimulation can be optimized for individualpatients with medically intractable epilepsy. With ma-chine and deep learning techniques, clinical and ECoG datafeatures may be identified that can direct personalized neu-rostimulator detection and stimulation programming. Ad-ditional work to define the short- and long-termmechanism(s) of action may help to determine the optimalapplication of these devices.

AcknowledgmentThe authors thank the patients and families for participating inthe RNS System trials. They also thank the members of theData Safety Monitoring Board, who were responsible forindependently monitoring the safety of interventions byreviewing data during the RNS System trials, and membersof the SUDEP Analysis Committee, who were responsible forreviewing data regarding any deaths that occur for participantsparticipating in the RNS System trials. Data Safety MonitoringBoard: Roger Porter, MD (chair), Gary Mathern, MD, JoanConry, MD, John “Jack” Pellock, MD (in memoriam), LoreneNelson, PhD, and Dan Bloch, PhD. SUDEP AnalysisCommittee: W. Allen Hauser, MD (chair), Thaddeus Walczak,MD, and Terri Haddix. In addition, they thank the followingindividuals who served as clinical study coordinators andcontributed to the research conducted (protocol procedures,data collection, and data entry): California Pacific MedicalCenter, San Francisco, CA. Douglas Raggett, RN, and Annavon Bakonyi, LVN, CCRC; Augusta University, Augusta, GA:Patty Ray, PhD; Henry Ford Hospital, Detroit, MI: HelenFoley, Carla Sandles, and Kelly Tundo, RN, BSN; SwedishNeuroscience Institute, Seattle, WA: Caryl Tongco, CCRP;Mayo Clinic Arizona, Scottsdale, AZ: Erica Boyd, RN, BSN;Johns Hopkins Medicine, Baltimore, MD: Joanne Barnett andPam Coe; Keck School of Medicine of USC, Los Angeles, CA:Guadalupe Corral-Leyva and Sandra Oviedo: Yale UniversitySchool of Medicine, New Haven, CT: Jennifer Bonito; Mayo

Clinic Florida, Jacksonville, FL: Karey Doll, PhD, BSN, RN,and Sabrina Selman; RushUniversityMedical Center, Chicago,IL: Diana Miazga; Columbia University Medical Center, NewYork, NY: Camilla Casadei; University of Texas SouthwesternMedical Center, Dallas, TX: Nasreen Sayed, MS; ClevelandClinic Foundation, Cleveland, OH: Chenett Greer, MEd,CCRP, Xiaoming Zhang, PhD, and Michael Mackow, RN;Geisel School of Medicine at Dartmouth, Hanover, NH: FaithAlexandre, CCRP; Indiana University School of Medicine,Indianapolis, IN: Abigail Klaehn, RN, BSN, and Linda Perdue;Massachusetts General Hospital, Boston, MA: S. AnthonySiena; Mayo ClinicMinnesota, Rochester, MN: Karla Crockettand Cindy Nelson; Medical University of South Carolina,Charleston: Becky Hamrick; Oregon Health & ScienceUniversity, Portland, OR: Chad Sorenson; Nicklaus Children’sHospital, Miami, FL. Tami Quintero, BS, CCRC; SaintBarnabas Medical Center, Livingston, NJ: Elaine DeCarlo,RN, and Jade Misajon, RN; University of Rochester MedicalCenter, Rochester, NY: Noreen Connelly, MS, JD, CRCC, andDiane Smith, CCRP; University of Wisconsin Hospital &Clinics, Madison, WI: Andrea Maser and ChristopherRoginski; Baylor College of Medicine, Houston, TX: RonnieS Tobias, DNP, ANP-C; EmoryUniversity School ofMedicine,Atlanta, GA: Yvan A Bamps, PhD, Diane Teagarden, APRN-BC, ANP, MSN, and Emilee Wehunt; George WashingtonUniversity School ofMedicine &Health Sciences,Washington,DC: Diane Rothrock and Stacy Tam; Weill Cornell MedicalCollege, New York, NY: Bill Nikolov, MD; University ofVirginia School of Medicine, Charlottesville, VA: Bruce Palmerand Stacy Thompson, RN, BSN, CCRC; University of Florida,Gainesville, Gainesville, FL: Amanda James; and Wake ForestUniversity Health Sciences, Winston-Salem, NC: JessicaDimos. Douglas R. Labar,MD, PhD, is deceased. The statisticalanalysis was performed by Tami Crabtree and Brian Johnson,Advance Research Associates Inc, Santa Clara, CA.

Study fundingNeuroPace, Inc. provided funding for the clinical study and isresponsible for the study design. All investigator authors wereresponsible for data collection. The sponsor, lead author, andother investigator authors contributed to data interpretationand preparation/review of the manuscript.

DisclosureD. Nair has received travel or speaker honorarium from Med-tronic, has consulted for NeuroPace, has been on the speakers’bureau forNeuroPace, has received research effort from theNIHand NeuroPace, and has received research support from BrainSentinel andNeuroPace. K. Laxer reports no disclosures relevantto the manuscript. P. Weber has consulted for NeuroPace. A.Murro and Y. Park report no disclosures relevant to the manu-script. G. Barkley has been on the speakers’ bureau for Neuro-Pace and has received research support from the NIH andNeuroPace. B. Smith has received travel and honorarium forbeing on the scientific advisory board for NeuroPace SK LifeScience and UCB, has received research effort from NeuroPace,

e1252 Neurology | Volume 95, Number 9 | September 1, 2020 Neurology.org/N

and is an active clinician whowill be prescribing the RNS Systemas a treatment option. R. Gwinn, M. Doherty, and K. Noe reportno disclosures relevant to the manuscript. R. Zimmerman hasconsulted for Medtronic on robotic instruments. G. Bergey hasbeen an associate editor for Neurotherapeutics. W. Anderson hasserved on the advisory board of Longeviti, has consulted forGlobus Medical, and has received research support from theNIH.C.Heck has received research support fromNeuroPace. C.Liu, R. Lee, T. Sadler, and R. Duckrow report no disclosuresrelevant to the manuscript. L. Hirsch has received researchsupport to Yale University for investigator-initiated studies fromMonteris Medical, Upsher-Smith Laboratories, and The DanielRaymondWongNeurology Research Fund at Yale; consultationfees for advising from Adamas Pharmaceuticals, AquestiveTherapeutics, CeriBell, Eisai Co, Medtronic, and UCB; royaltiesfrom Neurology and Wiley; and honorarium for speaking forNeuroPace. R. Wharen reports no disclosures relevant to themanuscript. W. Tatum has received a stipend as Editor-in-Chiefof Epilepsy Behavior Case Report, been awarded and pendingpatents, received royalties from Demos Publishers Inc andSpringer Publishing, received research support from Eisai Co(pending) and the Martin Family Foundation (in-kind dona-tion), and served as an expert witness on behalf of the EpilepsyFoundation of America (EFA), monies donated to EFA. S. Sri-nivasan:was the principal investigator at Columbia for the RNSSystem LTT study, sponsored by NeuroPace. G. McKhann hasserved on the publication committee of Stereotactic Laser Ab-lation for Mesial Temporal Lobe Epilepsy (SLATE) trial andserved as an investigator in the RNS System LTT study, spon-sored by NeuroPace. M. Agostini participated in the RNS Sys-tem clinical trials, sponsored by NeuroPace. A. Alexopoulosreports no disclosures relevant to the manuscript. B. Jobst hasreceived research support from the Centers for Disease Controland Prevention, Defense Advanced Research Projects Agency,Eisai Co, Medtronic, the National Science Foundation, Neuro-Pace, and Sunovion. D. Roberts has served on the advisoryboard/panel of Neurosurgery, Journal of Neurosurgery, Neurologiamedico-chirurgica, Zentralblatt fur Neurochirurgie, and Journal ofNeurologic Surgery Part A; has served on the editorial boards ofNeurosurgery, Journal of Neurosurgery, and World Neurosurgery;has served as editor of Neurosurgical Focus and Stereotactic andFunctional Neurosurgery; has awarded and pending patents; hasconsulted for the Department of Neurosurgery at Brigham andWomen’s Hospital; is cofounder and chief medical officer ofInSight Surgical Technologies LLC (no salary); has receivedresearch support Carl Zeiss Meditec, DUSA Pharmaceuticals,Medtronic, and the NIH; and has stock or stock options in ODSMedical. V. Salanova was/is the principal investigator at IndianaUniversity for the RNS System pivotal study and postapprovaltrial, sponsored by NeuroPace; the Stimulation of the AnteriorNucleus of the Thalamus for Epilepsy (SANTE) trial; theSLATE trial; and the NIH Radiosurgery vs Open Surgery forEpilepsy (ROSE) trial. T. Witt and S. Cash report no disclosuresrelevant to the manuscript. A. Cole has consulted for Biogen,Blackfynn, Boston Pharmaceuticals, Pfizer, Sage Therapeutics,and Takeda; received support for travel to an advisory meetingfor NeuroPace; received speaking fees from Genentech; and

served on data monitoring boards for Medtronic and OvidTherapeutics. G. Worrell is a founder of and owns stock inCadence Neuroscience. B. Lundstrom has served as an unpaidconsultant for Cadence Neuroscience, which is co-owned byMayo Clinic. J. Edwards reports no disclosures relevant to themanuscript. J. Halford has consulted for Cavion, NCGS Inc,Philips, and SK Life Science and has received research supportfrom Greenwich Biosciences, Brain Sentinel, Philips, SK LifeScience, Takeda, and The Epilepsy Study Consortium. D.Spencer has consulted for NeuroPace and receives travel orspeaker honorarium fromNeuroPace. L. Ernst received a 1-timehonorarium from NeuroPace for speaking at an educationalsymposium, and Oregon Health & Science University receivedfinancial support from NeuroPace for participation in the LTTStudy. C. Skidmore has received research support from Cavion,Engage Therapeutics, Medtronic Navigation, Neurelis, Neuro-pace, UCB Biopharma SPRL, SK Life Science, the NIH, UCBBiosciences, and Xenon Pharmaceuticals and has consulted forNeuroPace. M. Sperling has served as editor-in-chief for Epi-lepsia; consulted for Medtronic (paid to Thomas JeffersonUniversity); received research support from Cavion, Eisai, En-gage Therapeutics, Medtronic, Neurelis, Pfizer, SK Life Science,Takeda, and UCB Pharma (paid to Thomas Jefferson Univer-sity); and received publishing royalties from Oxford UniversityPress. I. Miller has received research support, travel funds, orconsulting fees from Biomarin, Dravet Syndrome Foundation,Greenwich Biosciences, Hope for HH Foundation, InsysTherapeudics, Insightec, NeuroPace, Neurelis, Tuberous Scle-rosis Alliance, Ultragenyx, Upsher-Smith, and Zogenix. E. Gellerhas served as an investigator for the RNS System clinical trials,sponsored by NeuroPace; has consulted for NeuroPace; hasbeen on the speakers’ bureau for NeuroPace and Liva Nova; andprescribes and programs the RNS System in clinical practice. M.Berg during the past 5 years has participated in research studiesas a principal investigator or subinvestigator sponsored by USFDA, American Epilepsy Society, Epilepsy Foundation ofAmerica, NeuroPace Inc, Sunovian, Upsher-Smith Labs, Lund-beck, Pfizer, King Pharmacetuicals, Sage Therapeutics, Biogen,and Acorda Therapeutics. He is part owner of the followingstartups: PharmAdva LLC and Jemsico LLC. A. Fessler, P.Rutecki, and A. Goldman report no disclosures relevant to themanuscript. E. Mizrahi has received research support fromNeuroPace and the US Department of Defense and royaltiesfrom McGraw-Hill Medical, Demos Medical Publishing,UpToDate, and Wolters Kluwers Publishers. R. Gross serves asa consultant to NeuroPace, Inc and receives compensation forthese services. NeuroPace develops products related to the re-search described in this article. The terms of this arrangementhave been reviewed and approved by Emory University in ac-cordance with its conflict of interest policies. In addition, Dr.Gross has consulted for Abbott, Boston Scientific, Clearpoint,Medtronic, NeuroPace, St. Jude Medical, and Zimmer Biometand received research support from the American Epilepsy So-ciety, Citizens United for Research in Epilepsy, Defense Ad-vanced Research Projects Agency, Mirkowski Foundation, NIH,and National Science Foundation. D. Shields has consulted,gratis, for Samitaur Medical Technologies and receives funding

Neurology.org/N Neurology | Volume 95, Number 9 | September 1, 2020 e1253

support as chief clinical investigator from US Army MedicalResearch andMateriel Command. T. Schwartz has consulted forIntegra and is an investor in Mivi Neuroscience. D. Labar isdeceased; disclosures are not included for this author. N.Fountain has received research support from Biogen, GWPharma, Medtronic, Neuropace, SK Life Science, UCB, andXenon and has been a medical monitor for Cerebral Thera-peutics and Medtronic. W. Elias has received research supportfrom Insightec. P. Olejniczak has been on the speakers’ bureaufor UCB Pharma. N. Villemarette-Pittman has been the man-aging editor of the Journal of the Neurologic Sciences (JNS) andreceived part of her salary and a travel honorarium from Elsevierfor the annual JNS board meeting. S. Eisenschenk reports nodisclosures relevant to themanuscript. S. Roper has consulted forMedtronic. J. Boggs has received research support through LivaNova, Medtronic, NeuroPace, and UCB and has served on theadvisory board of SK Life Science. T. Courtney certifies that shehas equity ownership/stock options with NeuroPace and is anemployee of NeuroPace. T. Sun certifies that she has equityownership/stock options with NeuroPace, has been an em-ployee of NeuroPace, and is currently a consultant for Neuro-Pace. C. Seale, K. Miller, T. Skarpaas, andM.Morrell certify thatthey have equity ownership/stock options with NeuroPace andare employees of NeuroPace. Go to Neurology.org/N for fulldisclosures.

Publication historyReceived by Neurology March 21, 2019. Accepted in final formMarch 6, 2020.

Appendix Authors

Name Location Contribution

Dileep R.Nair, MD

Cleveland ClinicFoundation, OH

Major role in theacquisition of data;analysis or interpretationof the data; drafting/revising manuscript forintellectual content

Kenneth D.Laxer, MD

California Pacific MedicalCenter, San Francisco

Major role in theacquisition of data

Peter B.Weber, MD

California Pacific MedicalCenter, San Francisco

Major role in theacquisition of data

Anthony M.Murro, MD

Augusta University, GA Major role in theacquisition of data

Yong D. Park,MD

Augusta University, GA Major role in theacquisition of data

Gregory L.Barkley, MD

Henry Ford Hospital,Detroit, MI

Major role in theacquisition of data

Brien J.Smith, MD

Ohio HealthNeuroscience, Columbus,OH

Major role in theacquisition of data

Ryder P.Gwinn, MD

Swedish NeuroscienceInstitute, Seattle, WA

Major role in theacquisition of data

Michael J.Doherty, MD

Swedish NeuroscienceInstitute, Seattle, WA

Major role in theacquisition of data

Appendix (continued)

Name Location Contribution

Katherine H.Noe,MD, PhD

Mayo Clinic Arizona,Scottsdale

Major role in theacquisition of data

Richard S.Zimmerman,MD

Mayo Clinic Arizona,Scottsdale

Major role in the acquisitionof data; drafting/revisingmanuscript for intellectualcontent

Gregory K.Bergey, MD

Johns Hopkins Medicine,Baltimore, MD

Major role in the acquisitionof data; drafting/revisingmanuscript for intellectualcontent

William S.Anderson,MD, PhD

Johns Hopkins Medicine,Baltimore, MD

Major role in theacquisition of data

ChristianneHeck, MD

Keck School of Medicineof USC, Los Angeles, CA

Major role in theacquisition of data

Charles Y.Liu, MD, PhD

Keck School of Medicineof USC, Los Angeles, CA

Major role in theacquisition of data

Ricky W. Lee,MD

Via Christi EpilepsyCenter, Wichita, KS

Major role in theacquisition of data

Toni Sadler,PA-C

Via Christi EpilepsyCenter, Wichita, KS

Major role in theacquisition of data

Robert B.Duckrow, MD

Yale University School ofMedicine, New Haven, CT

Major role in theacquisition of data

Lawrence J.Hirsch, MD

Yale University School ofMedicine, New Haven, CT

Major role in theacquisition of data;drafting/revisingmanuscript for intellectualcontent

Robert E.Wharen, Jr.,MD

Mayo Clinic Florida,Jacksonville

Major role in theacquisition of data

WilliamTatum, DO

Mayo Clinic Florida,Jacksonville

Major role in theacquisition of data

ShraddhaSrinivasan,MD

Columbia UniversityMedical Center, New York,NY

Major role in theacquisition of data;drafting/revisingmanuscript for intellectualcontent

Guy M.McKhann,MD

Columbia UniversityMedical Center, New York,NY

Major role in theacquisition of data

Mark A.Agostini, MD

University of TexasSouthwestern MedicalCenter, Dallas

Major role in theacquisition of data

Andreas V.Alexopoulos,MD

Cleveland ClinicFoundation, OH

Major role in theacquisition of data

Barbara C.Jobst, MD

Geisel School of Medicineat Dartmouth, Hanover,NH

Major role in theacquisition of data

David W.Roberts, MD

Geisel School of Medicineat Dartmouth, Hanover,NH

Major role in theacquisition of data

VicentaSalanova, MD

Indiana University Schoolof Medicine, Indianapolis

Major role in theacquisition of data

e1254 Neurology | Volume 95, Number 9 | September 1, 2020 Neurology.org/N

Appendix (continued)

Name Location Contribution

Thomas C.Witt, MD

Goodman Campbell Brainand Spine, Indianapolis,IN

Major role in theacquisition of data

Sydney S.Cash, MD,PhD

Massachusetts GeneralHospital, Boston

Major role in theacquisition of data

Andrew J.Cole, MD

Massachusetts GeneralHospital, Boston

Major role in theacquisition of data

Gregory A.Worrell, MD,PhD

Mayo Clinic Minnesota,Rochester

Major role in the acquisitionof data; drafting/revisingmanuscript for intellectualcontent

Brian N.Lundstrom,MD, PhD

Mayo Clinic Minnesota,Rochester

Major role in theacquisition of data;drafting/revisingmanuscript for intellectualcontent

Jonathan C.Edwards, MD

Medical University ofSouth Carolina,Charleston

Major role in theacquisition of data

Jonathan J.Halford, MD

Medical University ofSouth Carolina,Charleston

Major role in theacquisition of data

David C.Spencer, MD

Oregon Health & ScienceUniversity, Portland

Major role in theacquisition of data

Lia Ernst, MD Oregon Health & ScienceUniversity, Portland

Major role in theacquisition of data

ChristopherT. Skidmore,MD

Thomas JeffersonUniversity, Philadelphia,PN

Major role in theacquisition of data

Michael R.Sperling, MD

Thomas JeffersonUniversity, Philadelphia,PN

Major role in theacquisition of data;drafting/revisingmanuscript for intellectualcontent

Ian Miller,MD

Nicklaus Children’sHospital, Miami, FL

Major role in theacquisition of data

Eric B. Geller,MD

Saint Barnabas MedicalCenter, Livingston, NJ

Major role in theacquisition of data

Michel J.Berg, MD

University of RochesterMedical Center, NY

Major role in theacquisition of data

A. JamesFessler, MD

University of RochesterMedical Center, NY

Major role in theacquisition of data

Paul Rutecki,MD

University of WisconsinHospital and Clinics,Madison

Major role in theacquisition of data

Alica M.Goldman,MD, PhD

Baylor College ofMedicine, Houston, TX

Major role in theacquisition of data

Eli M.Mizrahi, MD

Baylor College ofMedicine, Houston, TX

Major role in theacquisition of data

Robert E.Gross, MD,PhD

Emory University Schoolof Medicine, Atlanta, GA

Major role in theacquisition of data

Appendix (continued)

Name Location Contribution

Donald C.Shields, MD

George WashingtonUniversity School ofMedicine and HealthSciences, Washington, DC

Major role in theacquisition of data

Theodore H.Schwartz,MD

Weill Cornell MedicalCollege, New York, NY

Major role in theacquisition of data

Douglas R.Labar, MD,PhD

Weill Cornell MedicalCollege, New York, NY

Major role in theacquisition of data

Nathan B.Fountain, MD

University of VirginiaSchool of Medicine,Charlottesville

Major role in theacquisition of data

W. Jeff Elias,MD

University of VirginiaSchool of Medicine,Charlottesville

Major role in theacquisition of data

Piotr W.Olejniczak,MD, PhD

Louisiana State UniversityHealth Sciences Center,New Orleans

Major role in theacquisition of data

Nicole R.Villemarette-Pittman, PhD

Louisiana State UniversityHealth Sciences Center,New Orleans

Major role in theacquisition of data;drafting/revisingmanuscript for intellectualcontent

StephanEisenschenk,MD

University of Florida,Gainesville,

Major role in theacquisition of data

Steven N.Roper, MD

University of Florida,Gainesville,

Major role in theacquisition of data;drafting/revisingmanuscript for intellectualcontent

Jane G.Boggs, MD

Wake Forest UniversityHealth Sciences, Winston-Salem, NC

Major role in theacquisition of data

Tracy A.Courtney, BS

NeuroPace, Inc, MountainView, CA

Design orconceptualization of thestudy; analysis orinterpretation of the data

Felice T. Sun,PhD

NeuroPace, Inc, MountainView, CA

Design orconceptualization of thestudy; analysis orinterpretationof the data

Cairn G.Seale, MS

NeuroPace, Inc, MountainView, CA

Design orconceptualization of thestudy

Kathy L.Miller, BS

NeuroPace, Inc, MountainView, CA

Analysis or interpretationof the data

Tara L.Skarpaas,PhD

NeuroPace, Inc, MountainView, CA

Analysis or interpretationof the data; drafting/revising manuscript forintellectual content

Martha J.Morrell, MD

NeuroPace, Inc, MountainView, CA; StanfordUniversity, Palo Alto, CA

Design orconceptualization of thestudy; analysis orinterpretation of the data;drafting/revisingmanuscript for intellectualcontent

Neurology.org/N Neurology | Volume 95, Number 9 | September 1, 2020 e1255

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Appendix 2 Coinvestigators

Coinvestigators are listed at links.lww.com/WNL/B153

e1256 Neurology | Volume 95, Number 9 | September 1, 2020 Neurology.org/N

DOI 10.1212/WNL.00000000000101542020;95;e1244-e1256 Published Online before print July 20, 2020Neurology 

Dileep R. Nair, Kenneth D. Laxer, Peter B. Weber, et al. epilepsy

Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal

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